Theoretical Insights into the Catalytic Mechanism of N-Heterocyclic

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Theoretical Insights into the Catalytic Mechanism of N-Heterocyclic Olefins in Carboxylative Cyclization of Propargyl Alcohol with CO2 Weiyi Li, Na Yang, and Yajing Lyu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00559 • Publication Date (Web): 06 Jun 2016 Downloaded from http://pubs.acs.org on June 7, 2016

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The Journal of Organic Chemistry

Theoretical Insights into the Catalytic Mechanism of N-Heterocyclic Olefins in Carboxylative Cyclization of Propargyl Alcohol with CO2 Weiyi Li*,† Na Yang,‡ and Yajing Lyu† †

School of Science, Xihua University, Chengdu, Sichuan, 610039, P. R. China.

‡

Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang, 621900, P. R. China

CORRESPONDING AUTHOR FOOTNOTE Dr. Weiyi Li Address: School of Science, Xihua University, Chengdu, Sichuan, 610039, P. R. China.

E-mail address: [email protected];

Tel: +86-028-87727663;

Fax: +86-028-87727663;

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ACS Paragon Plus Environment


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Abstract. The mechanism of carboxylative cyclization of propargyl alcohol with CO2 catalyzed by N-Heterocyclic Olefins (NHOs) has been studied by density functional theory (DFT) calculations. The calculations reveal that the catalytic reaction trends to undergo the NHO-mediated basic ionic pair mechanism, in which free NHO primarily plays as a basic precursor to trigger the carboxylative of propargyl alcohol with CO2, leading to a [NHOH]+[carbonate]− ion pair intermediate. Then, the catalytic cycle turns on, including isomerization of [NHOH]+[carbonate]− ion pair intermediate, intramolecular nucleophilic addition of carbonate oxygen anion to alkynyl group and protonation of alkenyl carbon anion with an external molecule propargyl alcohol. Molecule orbital and nature population analysis disclose that the preference for basic ionic pair mechanism is due to the favorable orbital and charge interactions between the α-carbon atom of NHO and the hydroxyl hydrogen of propargyl alcohol. The [NHOH]+ cation is proved to be crucial for stabilizing [carbonate]− anion, which allows the reaction proceeding through a thermodynamically more stable pathway. The investigations on substituent effect of NHOs predict that N-substituents with the large electron-donating and bulky steric effect might improve the catalytic activity of NHOs for the reaction.

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1. Introduction Nowadays, the catalytic transformation of carbon dioxide (CO2) is of increasing interest for producing highly value-added chemicals, such as methane,1 methanol,2 formic acid,3 and cyclic carbonates4 etc., because CO2 is both regarded as a greenhouse gas causing global warming problems and a highly abundant, inexpensive, nontoxic, nonflammable, and renewable C1 resource.5 However, the thermodynamical stability of CO2 is still one of the roadblocks on the way to its utilization. Consequently, the development of more powerful and efficient catalysts for the activation of CO2 is of great importance and a long-standing goal for chemists. Very recently, the alkylidene derivatives of the well-known N-heterocyclic carbenes (NHCs), termed N-heterocyclic olefins (NHOs), have emerged as a new class of valuable organocatalysts.6 Due to the aromatization of the N-heterocyclic ring in N,N’-disubstituted-2-methylene imidazolines, the nucleophilicity and basicity of the α-carbon atoms in NHOs are often stronger than those of the carbene centers in NHCs.7 Thus, NHOs and their derivatives have been established as a prevalent family of end-on ligands in transition metal coordination7,8 and organocatalysts in CO2 fixation and polymerization reactions.9 In 2013, Lu and co-workers reported the synthesis of a serials of NHOs using 2-methyl imidazolium iodide as a starting material (Scheme 1, reaction 1).9a The activation of NHO to CO2 is proved by the formation of zwitterionic NHO−CO2 adducts, in which the linear geometry of O=C=O at ground state is changed to be bent with an O−C−O angle of 127.7º~129.9º.9a The analogue bent geometries of O=C=O moiety are observed in

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other CO2-based metal complexes, such as nickel(0),10a,b cobalt(I),10c and Rh(I),10d etc., NHC−CO211a~c and guanidines−CO2 adducts.11d On the other hand, the resultant NHO−CO2 adducts are also found to be very effective in promoting carboxylative cyclization of propargylic alcohols with CO2 to give α-alkylidene cyclic carbonates (Scheme 1, reaction 2),9a which are versatile intermediates or precursors in organic synthesis and polymer chemistry.12 With respect to the already existing metallic catalysts (e.g. Ru,13a Co,13b Cu,13c,d Pd13e and Ag13f,g species) used for the reaction, organocatalysts,

which

have

advantages of

being

more

inexpensive

and

environmentally friendly, have attracted unprecedented attention over the last decade. Among the reported organocatalytic systems, including nBu3P,14 guanidines,15 NHC−CO216 and P-Yilde adducts17, NHO−CO2 adducts also show the comparable or better catalytic effect on improving the yield of the product, accelerating the reaction rate, lowering the catalyst loading and expanding the substrate scope of propargylic alcohols.

Scheme 1 Synthesis of NHO−CO2 Adducts and Their Application in Catalyzing Carboxylative Cyclization of Propargylic Alcohols with CO2

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Although NHO−CO2 adducts exhibit high catalytic potential in carboxylative cyclization reaction, the actual active species and the detailed catalytic mechanisms are ambiguous. This is because the decomposition of NHO−CO2 adducts to free NHOs and CO2 is inevitable as reaction temperature increases.9a Both NHO−CO2 adducts and free NHOs have a certain catalytic activity and might promote the reaction. The analogue phenomena are observed in a number of NHCs-catalyzed CO2 transformations, of which catalytic mechanisms have been successfully elucidated by means of quantum chemistry calculations.18 In terms of this fact, two possible mechanisms, differing in the catalytic role of free NHOs, were experimentally proposed for the present carboxylative cyclization reaction (Scheme 2).9a One is through a nucleophilic addition mechanism (Pathway 1), in which CO2 molecule is initially activated by the nucleophilic NHOs with the formation of NHO−CO2 adducts. Then, the carboxylate oxygen anion of NHO−CO2 adducts attacks the C≡C triple bond of propargyl alcohols to give an alkenyl anion intermediate IM1a. Finally, the protonation of alkenyl anion and intramolecular cyclization allow the production of α-alkylidene cyclic carbonates and the recovery of free NHOs. Alternatively, the catalytic reaction might proceed through a basic ionic pair mechanism (Pathway 2), where NHOs primarily plays as a base to abstract the hydroxyl hydrogen atom of propargyl alcohols, leading to a [NHOH]+[alkoxide]− ionic pair intermediate IM1b. The alkoxide anion with high nucleophilicity can easily capture one molecule CO2 to form a [NHOH]+[carbonate]− ionic pair intermediate IM2b. From IM2b, the intramolecular nucleophilic addition from the

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carbonate anion to C≡C triple bond and the pronation of the alkenyl anion with [NHOH]+ cation lead to the formation of α-alkylidene cyclic carbonate and regeneration of free NHOs. In order to clarify the real role of free NHOs, some deuterium labelling isotope analysis was also conducted by Lu and co-workers.9a However, the limited experimental results are too insufficient to determine the actual reaction course and understand the catalytic role of NHOs.

Scheme 2 Plausible Catalytic Cycles for Carboxylative Cyclization of Propargyl Alcohols with CO2 Catalyzed by NHOs.

Because of great potential of NHOs in synthetic chemistry and lack of investigation on

their

activation

mechanisms,

a

comprehensive

theoretical

study

on

NHOs-catalyzed carboxylative cyclization of propargylic alcohols with CO2 was performed in this work. Through a detailed mechanistic studies, we hope to provide important insights into the understanding of the catalytic role of NHOs in

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carboxylative cyclization reactions, which may optimize/improve reaction condition, characterize NHOs catalytic systems and extended their application in a broader range of CO2 transformations.

2. Computational methods To disclose the catalytic mechanism of NHOs in carboxylative cyclization of propargylic alcohols with CO2, a DFT calculation on such reaction was performed with Gaussian 09 program.19 All geometries of the reactants, products, intermediates (IM) and transition states (TS) involved in the present mechanistic study were fully optimized in CH2Cl2 solvent (experimentally used) with the continuum solvation model (SMD20) at the M06-2X21/6-31+G*22 level of theory. This method has already been examined to be efficient and reliable in our previous study on the structure-activity relationship of free NHOs and NHO−CO2 adducts with various kinds of substituents on the N- and C-positions of the imidazolium ring.23 The vibrational frequency calculations at the same level of theory were carried out to characterize each optimized-structure is an intermediate (with none imaginary frequency) or a transition state (with one imaginary frequency) and obtain the thermal corrections at 298 K. Intrinsic reaction coordinates (IRC24) scans were conducted when necessary to check the transition state correctly connects the two relevant minima. To improve the accuracy of the energy, the single-point energy of each optimized-structure was calculated at the M06-2X (SMD, CH2Cl2)/6-311++G** level. The relative free energy (∆Gsol) was obtained by combining the single-point energy

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with Gibbs free energy correction at the M06-2X/6-31+G* level. In addition, an adjustment for the change in standard state from 1 atm to 1 M concentration of RT ln(24.5), 1.9 kcal mol−1, was applied for all the species in solution. Since the present reaction involves the component changes, the translation and rotational entropy loss in intermediates and transition states will be significantly overestimated if the separated reactants were used as the energy reference. Based on “the theory of free volume”,25a a correction of 2.6 kcal mol−1 per component change for a reaction [i.e., a reaction from m to n components has an additional correction of (n − m) × 2.6 kcal mol−1] was made as many earlier theoretical studies did.25b~d Unless otherwise specified, the relative free energy (∆Gsol, 298K, 1M) including the thermal correction, standard state correction and entropy correction was discussed in the main text. The relative enthalpy (∆Hsol) and relative free energy without entropy correction (∆Gsol, wec) are given in Supporting Information for references. In addition, natural bond orbital (NBO26) analysis on the key species was carried out to get an insight into the electronic properties of the system.

3. Results and Discussion 3.1 Background reaction without catalyst Initially, the reaction pathway for carboxylative cyclization of propargyl alcohol 1a with CO2 in the absence of catalysts was explored as an ideal benchmark to discuss the catalytic reaction under free NHOs or NHO−CO2 adducts. As shown in Figure 1, the uncatalyzed carboxylative cyclization reaction of 1a with CO2 is composed of

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three elementary steps. The first step is the carboxylative of 1a with CO2 through a concerted four-center b-TS1 (44.4 kcal mol−1), leading to b-IM1. Then, the hydroxyl group of the carbonate moiety orients toward the propargyl moiety in b-IM2, as the consequence of the C−O single bond rotation over b-TS2 (13.6 kcal mol−1). With this conformation, b-IM2 can be ready to undergo an intramolecular nucleophilic addition from the carboxyl oxygen atom to the C≡C triple bond, resulting in the ring-closure product 2a. This process via b-TS3 (50.6 kcal mol−1) contains the initial hydrogen transfer from the carboxyl group to the terminal carbon atom of the alkynyl group, followed by the nucleophilic attack of the carboxyl oxygen atom to the middle carbon atom of the alkynyl group. Although the formation of 2a is exoergic by 19.1 kcal mol−1 in free energy, the carboxylative cyclization of 1a with CO2 without catalysts should be kinetically not allowed under mild condition, as the energy barriers for the carboxylative and intramolecular cyclization steps are high up to 44.4 and 50.6 kcal mol−1, respectively.

Figure 1. Energy profile for uncatalyzed carboxylative cyclization of 1a with CO2 calculated at the M06-2X(SMD, CH2Cl2)/6-311++G**//M06-2X(SMD, CH2Cl2)/6-31 +G* level. 9



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3.2 Catalytic reaction mechanism In Lu’s experiment,9a the NHO−CO2 adduct (ImH2N2,6-iPrC6H3iPr) bearing 2,6-diisopropylphenyl and isopropyl groups on the N-positions of the imidazolium ring exhibited the highest activity in catalyzing carboxylative cyclization of 1a with CO2. Thus, all possible catalytic reaction mechanisms were explored in the presence of this NHO−CO2 adduct, which is in aim of determining the minimum energy reaction pathway (MERP) and the catalytic role of NHO−CO2 adducts or free NHOs in the reaction. For brevity, the energetics associated with the two catalytic cycles shown in Scheme 2 are discussed in details in what follows. The optimized-structures and relative energies for the relevant IMs and TSs involved in other mechanisms are provided in Supporting Information.

Pathway 1: Nucleophilic addition mechanism mediated by NHO−CO2 adduct The computed potential energy surface (PES) for the nucleophilic addition mediated by NHO−CO2 adduct is presented in Figure 2. Along this reaction pathway, a reactant-catalyst molecular complex 1 is initially formed, which lies 6.9 kcal mol−1 above the reference energy point. From complex 1, an intermolecular nucleophilic addition from the carboxylate oxygen anion of NHO−CO2 adduct to the C≡C triple bond of 1a takes place via TS1-2, pushing more electron density to the terminal carbon atom of the alkynyl group. The relative free energy of TS1-2 is predicted to be 34.7 kcal mol−1, implying that the nucleophilicity of the NHO−CO2 adduct might be insufficient. In the resultant IM 2, the large negative charge (−0.61 e) is accumulated

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on the alkenyl carbon anion, making this species unstable in thermodynamics. Subsequently, the hydroxyl hydrogen atom is snatched by the negatively charged alkenyl carbon anion via a five-membered-ring TS2-3 (37.5 kcal mol−1) to give an alkoxide anion IM 3 and release a free energy of 11.5 kcal mol−1. Since a high thermodynamic driving force usually leads to a lower energy channel for the proton transfer process, a single molecule of substrate 1a or water-assisted proton transfer from the hydroxyl oxygen atom to the alkenyl carbon anion was further considered, as alcohol and water molecules are well known proton shuttles in other areas of proton transfer process.27 The computed relative free energy of 1a or water-assisted six-membered-ring concerted TS2-3' and TS2-3'' is 31.3 and 29.3 kcal mol−1, respectively, which is expected to be lower that of TS2-3. Thus, both 1a and water could serve as the proton shuttle for accelerating the present proton transfer process. From IM 3, the following isomerization over the C−C single bond rotation TS3-4 (25.6 kcal mol−1) allows the nucleophilic alkoxide anion facing toward the carboxylate moiety in IM 4. With this conformation, the intramolecular cyclization with the generation of 2a-NHO adduct (IM 5, −3.2 kcal mol−1) can be easily formed through an intramolecular nucleophilic addition TS4-5, with a low energy barrier of 0.9 kcal mol−1. Finally, IM 5 experiences a C−C bond cleavage TS5-6 (9.8 kcal mol−1) to release product 2a and free NHO, and the subsequent carboxylation of free NHO with CO2 (TS-carboxylation, 0.6 kcal mol−1) will recover NHO−CO2 adduct. Alternatively, a branched channel from reactant complex 7 to product-catalyst complex 10 was also considered for the transformation of alkenyl anion IM 2 to product 2a and NHO−CO2

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adduct. Along this channel, the proton transfer from the hydroxyl oxygen atom to the alkenyl carbon anion is coupled with the insertion of one molecule CO2 into the forming alkoxide oxygen anion, resulting in a carboxylation IM 8. The free energy barrier for the formation of IM 8 via TS7-8 is predicted to be 39.3 kcal mol−1, which is higher than that of substrate 1a or water-assisted proton transfer process. Then, the intramolecular nucleophilic attack from the carboxyl oxygen anion to the sp2 hybrid alkenyl carbon atom occurs, which leads to the formation of product 2a and the regeneration of NHO−CO2 adduct. For this intramolecular cyclization step, the 1a-assisted addition-elimination mechanism (8→TS8-9→9→TS9-10→10) is found to be kinetically more favorable than the backside SN2 nucleophilic substitution mechanism (8→TS8-10→10). Because of the much higher energy barrier requested at TS7-8, this branched channel could be safely ruled out for the whole pathway. In addition, other nucleophilic addition mechanisms, such as the nucleophilic addition of NHO−CO2 adduct to 1a associated with the insertion of an external molecule CO2 into the alkynyl group (pathway 3, Figure S1), and the nucleophilic addition of free NHO to the C≡C triple bond of 1a (pathway 4, Figure S2), were computationally examined as well. Among these three nucleophilic addition mechanisms, the energy height of the highest point (EHHP) at TS1-2 (34.7 kcal mol−1) along pathway 1 is the lowest. Thus, it is clear that pathway 1 should be the MERP for the nucleophilic addition mechanism.

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Figure 2. Energy profile for carboxylative cyclization of 1a with CO2 along pathway 1 calculated at the M06-2X(SMD, CH2Cl2)/6-311++G**//M06-2X(SMD, CH2Cl2) /6-31+G* level.

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Pathway 2: Basic ionic pair mechanism mediated by NHO On the other hand, the basic ionic pair mechanism mediated by NHO was also conducted for the catalytic reaction. As shown in Figure 3, pathway 2 starts from the decarboxylation of NHO−CO2 adduct via a C−C bond cleavage TS, leading to the generation of free NHO and CO2. The free energy barrier of this decarboxylation step is 17.1 kcal mol−1, and the whole decarboxylation process is endergonic by 13.7 kcal mol−1. These results are well compatible with experimental observation that the decomposition of NHO−CO2 adduct to free NHO and CO2 takes place at 40 °C, and NHO−CO2 adduct and free NHO are in a dynamical equlibrium.9a Next, the resultant NHO and CO2 molecules approach with 1a, resulting in complex 11. From this termolecular molecule, the deprotonation of 1a by free NHO, coupled with the insertion of one molecule CO2 with the forming alkoxide oxygen anion, takes place at TS11-12. In comparison with the uncatalyzed carboxylative of 1a with CO2 via b-TS1 (44.4 kcal mol−1), the catalytic effect of free NHO is significant, as the relative free energy of TS11-12 is sharply reduced to 23.5 kcal mol−1. Additionally, we also tested the deprotonation of 1a by free NHO in the absence of CO2 (see Figure S4). This process needs to overcome a relatively higher energy barrier (24.5 kcal mol−1), suggesting that the concerted carboxylative of 1a with CO2 is slightly more favorable in kinetics. After cross TS11-12, an ionic pair IM 12 is formed, in which one hydrogen atom of [NHOH]+ cation simultaneously interacts with the carboxylate and hydroxyl oxygen atoms of [carbonate]− anion. The following isomerization of IM 12 via the C−O single bond rotation TS12-13 (8.8 kcal mol−1) makes one of the carboxylate

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oxygen atoms face toward the alkynyl group. This isomerization also alters the interactions between [NHOH]+ cation and [carbonate]− anion, giving a more stable ionic pair IM 13 (−0.3 kcal mol−1). From IM 13, the intramolecular nucleophilic addition of carboxylate oxygen anion to the alkynyl group occurs. The trans-conformational TS13-14 (19.7 kcal mol−1) is predicted to be energetically more preferred than the analogue TS13-14' (24.1 kcal mol−1) adopting cis configuration. This result is in good agreement with the X-ray crystal structure determination by Ikariya and co-workers14d that Z-configurational α-alkylidene cyclic carbonates were yielded in P(n-C4H9)3-catalyzed carboxylative cyclization of propargyl alcohols with supercritical CO2. Relative to the uncatalyzed intramolecular cyclization via b-TS3 (50.6 kcal mol−1), the relative free energy of TS13-14 is also remarkably lowered. After the intramolecular cyclization, the ring-closured carbonate IM 14 (18.0 kcal mol−1) is formed, in which the large negative charge (− 0.60 e) is accumulated on the alkenyl carbon anion as well. From IM 14, two scenarios for the protonation of alkenyl carbon anion are possible, because [NHOH]+ cation and excess 1a are both available proton sources in the reaction system. To complete the protonation of alkenyl carbon anion with the [NHOH]+ cation, the cyclic carbonate moiety in IM 14 first needs to undergo a conformational rotation TS14-15 (22.7 kcal mol−1), permitting the alkenyl carbon anion orienting toward the methyl group of [NHOH]+ cation in IM 15. Then, the hydrogen migration from the [NHOH]+ cation to the alkenyl carbon anion proceeds through a C−H bond cleavage TS15-16 (24.1 kcal mol−1), leaving a product-catalyst complex 16 (−2.7 kcal mol−1) behind. The isolation of 2a from complex 16 recovers

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free NHO and finishes the catalytic cycle shown in Scheme 2. Alternatively, when an external molecule 1a is employed as the proton donor, the interaction of the hydroxyl group of 1a with the alkenyl carbon anion of IM 14 forms a molecular complex 17. In this complex, the negative charge on alkenyl carbon anion is delocalized by the hydroxyl group of 1a, and thus the relative free energy of complex 17 is reduced by 2.9 kcal mol−1 relative to IM 14. Meanwhile, the O−H bond in complex 17 is weakened, as reflected by the smaller the Wiberg bond index (0.472 vs 0.771 in 1a). Consequently, the subsequent proton transfer from the hydroxyl group of 1a to the alkenyl carbon anion can easily occur, which is associated with the insertion of one molecule CO2 with the forming alkoxide oxygen anion, leading to a product-catalyst complex 18 (−10.9 kcal mol−1). Although the computed relative energy of TS17-18 is slightly lower than that of complex 17 by 1.0 kcal mol−1, the vibration frequency calculation confirms that TS17-18 is a first-order saddle point with a unique imaginary frequency of −760. 0 cm−1. This result is similar to the theoretical calculations on the proton transfer processes, suggesting that the PES around this area is very flat.28 Finally, the separation of 2a from complex 18 will regenerate IM 12. From Figure 3, it is apparent that the protonation of IM 14 with 1a is kinetically and thermodynamically more preferable than that with [NHOH]+ cation. The reason might be ascribe as the cleavage of O−H bond in 1a is more feasible than that of C−H bond in [NHOH]+ cation. As a result, the catalytic cycle of this basic ionic pair mechanism should be composed of three elementary steps: (i) isomerization of ionic pair IM 12 to IM 13; (ii) intramolecular nucleophilic cyclization of IM 13, leading to alkenyl carbon

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anion IM 14; and (iii) protonation of IM 14 with 1a to yield product 2a and regenerate IM 12. The free NHO primarily play as a strong base to trigger the generation of [NHOH]+ [carbonate]− ionic pair IM 12 in the carboxylative of 1a with CO2.

Figure 3. Energy profile for carboxylative cyclization of 1a with CO2 along pathway 2 calculated at the M06-2X(SMD, CH2Cl2)/6-311++G**//M06-2X(SMD, CH2Cl2) /6-31+G* level. 17



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Moreover, it should be mentioned that the other analogue basic ionic pair mechanism by employing NHO−CO2 adduct as the basic promoter was also comparatively studied (pathway 5, Figure S3). The calculations show that the deprotonation and carboxylative of 1a with CO2 promoted by NHO−CO2 adduct is more facile, with a low energy barrier of 8.4 kcal mol−1. However, the computed EHHP of 28.3 kcal mol−1 at the protonation step along this pathway is much higher than that in pathway 2. Thus, this ionic pair mechanism could be excluded as well. So far, the overall mechanism of the catalytic reaction is clear. For the nucleophilic addition mechanism along pathway 1, an EHHP of 34.7 kcal mol−1 is required at TS1-2, while a much lower one of 23.5 kcal mol−1 at TS11-12 is predicted for the basic ionic pair mechanism along pathway 2. The computed EHHP of 23.5 kcal mol−1 also qualitatively agrees with the experimental observations that the reaction could proceed under a temperature of 60 ºC and a CO2 pressure of 2.0 Mpa within 12 h.9a Therefore, we can conclude that the carboxylative cyclization of 1a with CO2 in the presence of NHO−CO2 adduct should adopt the NHO-mediated basic ionic pair mechanism rather the nucleophilic addition being catalyzed by NHO−CO2 adduct. For the NHO-mediated basic ionic pair mechanism, the [NHOH]+[carbonate]− ion pair IM 13 and intramolecular cyclization TS13-14 can be regarded as the turnover frequency intermediate (TDI29) and turnover frequency transition state (TDTS) in the catalytic cycle, respectively. The global energy span between the TDI and TDTS is 20.0 kcal mol−1, and the turnover frequency (TOF29) value of the catalytic cycle is calculated to be 4.9×101 h−1. These computed values are also in good agreement with the

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experimental result that the product 2a could be obtained in high yield (up to 98%) within the short period of reaction time (12 h).9a In addition, the rate constants for the two crucial steps (k1 for 1a + NHO−CO2→TS11-12 and k2 for IM 13→TS13-14) were also quantitatively estimated according to the conventional transition state theory,30a including the tunneling correction.30b Over the 278~328 K temperature range, the rate constants can be fitted by the following expressions: k1 (T) (in mol−1 dm3 s−1) = 2.899 ×106 exp (−59252/RT) and k2 (T) (in s−1) = 6.547×1012 exp (−82470/RT) (see Section S4 in Supporting Information for calculation details).

3.3 More insights into NHOs organocatalyst The understanding of catalytic reaction mechanisms motivated us to gain more insights into the catalytic activity of NHOs due to their great catalytic potential in promoting CO2 fixation reactions. Why basic ionic pair mechanism is more preferred to nucleophilic addition mechanism? According to the relevant literatures7,9a as well as the results of chemical reactivity index analysis31,32 (Table 1), both NHO−CO2 adduct and free NHO can be considered as strong nucleophiles (N > 3.0 eV).33 However, DFT calculations on the catalytic reaction suggest that the intermolecular nucleophilic addition from NHO−CO2 adduct or free NHO to the C≡C triple bond of 1a requires a high EHHP of 34.7 or 39.9 kcal mol−1. In contrast, the deprotonation of 1a by NHO-CO2 adduct or free NHO is relatively more facile, with a much lower EHHP of 8.4 or 23.5 kcal mol−1. To explain these computed results, molecular orbital (MO) and nature

19



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Page 20 of 36

population analysis (NPA) were performed on substrate 1a, NHO−CO2 adduct, free NHO.

Table 1.The electronic chemical potential µ, chemical hardness η, global electrophilicity ω, and global nucleophilicity N (all in eV) for the selected reactants, catalysts and IMs calculated at the M062x/6-311++G** level Species

µ

η

ω

N

CO2

−12.4

12.3

6.3

−1.5

1a

−9.3

9.0

4.8

1.7

NHO−CO2

−7.8

6.6

4.7

3.7

NHO [NHOH]+[carbonate]− 13 [NHOH]+

−5.6 −7.8 −14.3

5.3 6.6 7.9

3.0 4.6 13.1

5.4 3.7 −0.2

[carbonate]−

−1.0

5.8

0.1

7.5

From MO analysis (Figure 4), it is clear that the LUMO of 1a is predominantly contributed by the s orbital of the hydroxyl hydrogen atom, while the LUMO+1 orbital of 1a is mainly contributed by the empty π orbital of the alkynyl group. Hence, the charge transfer from the p orbital of the carboxylate oxygen anion in the HOMO of NHO−CO2 adduct or the p orbital of the α-carbon atom in the HOMO of free NHO to the empty π of the alkynyl group in the LUMO+1 orbital of 1a needs to overcome a higher energy gap (ca. 10.3 kcal mol−1 for the energy gap between LUMO+1 and LUMO of 1a). On the other hand, the NPA charge analysis (Scheme 3) shows that the middle carbon atom of the alkynyl group is negatively charged in 1a, which may not prefer to accept the nucleophilic attack from the negatively charged carboxylate oxygen anion in NHO−CO2 adduct or the α-carbon atom in free NHO. On the 20


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contrary, the hydroxyl hydrogen atom with the positive charge has good affinity to the carboxylate oxygen anion in NHO−CO2 adduct or the α-carbon atom in free NHO. Therefore, the activation energy barrier for the deprotonation of 1a by NHO−CO2 adduct or free NHO is calculated to be much lower. Furthermore, we also notice that the NPA charge on the middle carbon atom of the alkynyl group becomes positive in carbonate anion or [NHOH]+ [carbonate]− ionic pair IM 13, and the terminal carbon atom is more negatively charged. That is to say, π bonds of the alkenyl group are polarized to some extent in these species, which are certainly more susceptible to accept a nucleophilic attack from the carbonate oxygen anion, leading to the preference for the intramolecular cyclization step.

Figure 4. The visualization of the selected molecular orbitals of the NHO−CO2 adduct, free NHO and propargyl alcohol 1a.

21



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Scheme 3. The NPA Charge of the Key Species Are Labelled In Red (Positive) and Blue (Negative) Members.

How does the substituent effect of NHOs influence the catalytic reaction? Similar to NHCs,11a~b,34a the thermal stability of NHO−CO2 adducts and catalytic activity of NHOs are also related to the electronic and steric effect of N- and C-substituents on the imidazolium ring.9a Herein, four sets of NHOs (in Scheme 4) were employed to simulate the catalytic reaction, which is aiming of clarifying the substituent effect of NHOs on the catalytic reaction. The free NHO (ImH2N2,6-iPrC6H3iPr) used in mechanistic study was chosen as the reference system. As mentioned before, the catalytic cycle is triggered by the formation of [NHOH]+[carbonate]− IM 12 through NHO-mediated carboxylative of 1a with CO2, that is the initial reaction rate is influenced by the EHHP of TS11-12 (∆G1≠) relative to the separated NHO−CO2 adduct and 1a. After crossing this energy summit, the catalytic cycle can turn on. The IM 13 and TS13-14 in the intramolecular step are TDI and TDTS in the catalytic cycle, 22


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respectively, meaning that the TOF value is dependent on the global energy span (∆G2≠) between IM 13 and TS13-14. Accordingly, the values of ∆G1≠ and ∆G2≠ for these two crucial steps (1a + NHO−CO2→TS11-12 and IM 13→TS13-14) were calculated at the same level of theory. Since NHO−CO2 adducts, free NHOs and CO2 molecules are generally in reversible equilibriums, and NHO−CO2 adducts are thermodynamically more stable, the sum of free energies of NHO−CO2 adducts and 1a is set as the energy point reference.

Scheme 4. Selected NHOs with typical abbreviations34b in Simulation of Carboxylative Cyclization of 1a with CO2.

Initially, the effect of C-substituents on the catalytic reaction was investigated (Set A and B). The relationship between substituent R1 groups and free energy barriers in carboxylative and intramolecular steps is depicted in Figure 5(a) and 5(b), respectively. In the case of set A, the value of ∆G1≠ is gradually increased when the electron-withdrawing group is replaced by the electron-donating one. This result means that the introduction of electron-withdrawing groups on the C-positions of the

23



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Page 24 of 36

imidazolium ring will accelerate the catalytic carboxylative of 1a with CO2. The reason might be attributed to the weak nucleophilicity of free NHO that bears the electron-withdrawing C-substituent.23 In other words, the electron-withdrawing C-substituent can inhibit the competing side reaction (NHO + CO2 → NHO−CO2), leading to the preference for the desired carboxylative of 1a with CO2. However, the value of ∆G2≠ is also increased when the electron-withdrawing effect of R1 group is enhanced. This might be due to the fact that the stabilization interaction from [NHOH]+ cation to [carbonate]− anion is looser (See Section S5 in Supporting Information for the characterization of stabilization interactions between [NHOH]+ cation and [carbonate]− anion). Since the higher value of ∆G2≠ will lead to the lower TOF, the introduction of electron-withdrawing groups on the C-positions of the imidazolium ring might reduce the catalytic efficiency of NHOs. For set B, the trend for the value of ∆G1≠ is also monotonically increased when the electron-donating effect of the C-substituent is increased. The computed absolute values of ∆G1≠ in set B are lower, which might be due to the effect of N-substituent. The trend for the values of ∆G2≠ is not very regular, but it is general smoothly decreased like that in set A, except for the NHO with –CO2Me group. Based on the above results, we can predict that the catalytic effect of NHOs may not be improved by tuning the electronic effect of C-substituent on the imidazolium ring.

24


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Figure 5. Relationship between substituents of NHOs and free energy barriers (∆G1≠ and ∆G2≠) in steps of carboxylative of 1a with CO2 and intramolecular cyclization of IM 13.

Next, the effect of N-substituents was explored (Set C). As shown in Figure 5(c), the values of ∆G1≠ and ∆G2≠ are gradually reduced when the electron-donating effect of R2 group is increased. These results suggest that the N-substituents have an obvious influence

on

the

catalyst

activity.

The

N-substituents

with

the

strong

electron-withdrawing effect will seriously reduce the proton affinity of free NHOs and the stabilization between [NHOH]+ cation and [carbonate]− anion, and thus disfavor for both carboxylative and intramolecular processes. Relative to methyl and iso-propyl groups substituted NHOs, tert-butyl group substituted one performs better 25



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Page 26 of 36

catalytic effect on both carboxylative and intramolecular cyclization steps, which might be due to the stronger electron-donating effect and bulkier steric effect of tert-butyl group. The strong electron-donating effect will enhance the proton affinity of α-carbon atom, while the bulky steric effect will inhibit the competing capture of CO2 with the formation of the NHO−CO2 adduct, making the catalytic carboxylative of 1a with CO2 faster. Meanwhile, tert-butyl groups with the stronger electron-donating effect are also in favor of stabilizing the carbonate anion. Thus, the computed ∆G2≠ value of 20.0 kcal mol−1 is comparable with the reference system. On the contrary, the computed ∆G2≠ values of 22.6 and 21.9 kcal mol−1 for methyl and iso-propyl substituted NHOs are higher, which is also in line with the experimental observations that 2a was obtained with the lower yields (51% and 72%) when methyl and iso-propyl groups are introduced on the N-positions of the imidazolium ring, respectively.9a The above results indicate that both electronic and steric effect will influence on the catalytic activity of NHOs. Finally, the catalytic effect of NHOs bearing the saturated or unsaturated rings fused at the N- and C-positions was examined (Set D). Among these four free NHOs, ImDpylm NHO gives the satisfactory catalytic effect on both carboxylative (∆G1≠ = 19.8 kcal mol−1) and intramolecular cyclization (∆G2≠ = 20.4 kcal mol−1) processes. This result might be attributed to the sp2-hybridized carbon atoms as the weak electron-withdrawing groups that have a small impact on the proton affinity of the α-carbon atom in NHO and the stabilization interaction between the [NHOH]+ cation and [carbonate]− anion.

26


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4. Conclusions The catalytic mechanism of NHOs organocatalyst in carboxylative cyclization reaction of propargyl alcohol with CO2 has been comprehensively investigated with DFT calculations. The major conclusions are listed as follows: The calculations reveals that the catalytic reaction prefers to undergo the NHO-mediated basic ionic pair mechanism rather than the nucleophilic addition mechanism being catalyzed by the NHO−CO2 adduct. Thus, the NHO−CO2 adduct with the lower thermo stability for easily releasing free NHO should be chosen as the catalytic precursor for the reaction. The free NHO primarily plays as a basic promoter to trigger the carboxylative of propargyl alcohol with CO2, leading to the formation of the [NHOH]+[carbonate]− ion pair intermediate. Once this active species is generated, the

catalytic

cycle

can

easily

turn

on,

including

isomerization

of

e

[NHOH]+[carbonate]− ion pair intermediate, intramolecular nucleophilic attack of the oxygen anion to the alkynyl group and proton transfer from the external molecule propargyl alcohol to the alkenyl anion intermediate. MO and NPA charge analysis disclose that the preference for the basic ionic pair mechanism is due to the favorable orbital and charge interactions between the α-carbon atom of NHO and the hydroxyl hydrogen atom of propargyl alcohol. That is to say, the basicity of the catalyst rather than its nucleophilicity should be considered to be more significant for this kind of reaction. The investigations on substituent effect of NHOs show that N-substituents with the large electron-donating and bulky steric effect are crucial for the catalytic activity of NHOs, which may assist the experimenters to further modify NHO organocatalysts. 27



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Acknowledgment. The authors are grateful for the financial support from the National Natural Science Foundation of China (Nos. 21402158), the Scientific Research Fund of Education Department of Sichuan Province (Nos. 14ZB0131), the Key Scientific Research Found (Nos. Z1313319) and the Open Research Subject of Key Laboratory (Research center for advanced computation) of Xihua University (Nos. szjj2015-051).

Supporting Information Available: Computational details, optimized geometries, calculated energies and the full citation of Gaussian 09 program are available free of charge via the Internet at http://pubs.acs.org.

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(32) The global electrophilicity index ω, (Ref. 31c,d) which measures the stabilization energy when the system acquires an additional electronic charge ∆N from the environment, is given in terms of the electronic chemical potential µ and chemical hardness η by the following simple expression: (Ref. 31e) ω[eV] = (µ2/2η). Both quantities can be calculated in terms of the HOMO and LUMO electron energies, εH and εL, as µ ≈ (εH + εL)/2 and η ≈ (εL – εH), respectively. (Ref. 31f,g) The nucleophilicity index N, (Ref. 31b) based on the HOMO energies obtained within the Kohn–Sham scheme, is defined as N = EHOMO(Nu) − EHOMO(TCE). (Ref. 31b) The nucleophilicity is taken relative to tetracyanoethylene (TCE) as a reference, because it has the lowest HOMO energy in a large series of molecules already investigated in the context of polar cycloadditions.

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Graphic Abstract.

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Theoretical Insights into the Catalytic Mechanism of N-Heterocyclic

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